From a therapeutic standpoint, a large number of drugs are employed for their central nervous system action. Examples of such classes of agents are centrally acting analgesics, antineoplastic agents, cerebral ischemia protectants, and compensatory therapeutic agents for central disorders such as Alzheimer's or schizophrenia. Other examples include drugs targeted to a variety of central nervous system disorders.
The spinal (intrathecal/epidural) administration of the centrally acting drugs described above has been shown to have considerable therapeutic efficacy for the treatment of several clinical states including pain, spasticity, central nervous system tumors and infections. In particular, the epidural administration of opioid analgesics represents an important clinical tool for the management of acute and chronic pain states Yaksh, T. L., Noueihed, R. Y., Durant, P. A. C.: Anesthesiology 64:54-66 (1986). The drug most commonly employed is morphine. Its kinetics are characterized by slow onset and a prolonged residency time in cerebrospinal fluid (CSF) Payne, R.: Acta Anaestheiol. Scand. (31, suppl.) 85:38-46 (1987). Sufentanil and other anilinopiperidines may be important alternatives to morphine by this route. These are powerful mu opioid receptor agonists that appear to have a higher intrinsic efficacy than morphine Stevens, C. W., Yaksh T. L.: J. Pharmacol. Exp. There. 250:1-8 (1989) and have higher lipid partition coefficients, indicating that these drugs will have a rapid onset.
Unfortunately, neuraxial administration of centrally acting drugs has some drawbacks. Most problematic is the fact that these drugs also achieve significant plasma concentrations after their administration. For example, epidurally administered drugs have several routes for redistribution: (a) movement into fat; (b) passage through the dura and thence into the spinal cord; and (c) most importantly, movement into the thin-walled epidural venous plexus and thence into the systemic circulation Yaksh, T. L.: Pain 11:293-346 (1981). Thus, following spinal administration of sufentanil or alfentanil, there are prominent blood concentrations of opioids early on which correspond with the rapid egress of drug from the epidural space Sabbe M. B., Yaksh T. L.: J. Pain and Symp. Manag. in press (1990). This vascular redistribution clearly results in powerful and acute supraspinal side effects. Such side effects are often serious and sometimes fatal.
A key goal of the present invention has been to develop improved methods that will allow the routine, acute and chronic administration of agents into the neuraxis via intraventricular, epidural, intrathecal, intrasisternal and related routes (hereafter jointly referred to as neuraxial routes) without the redistribution problem detailed above. An ideal therapeutic modality requires: (a) the prolonged and predictable presence of therapeutic concentrations of neuraxially-administered drugs at or near their sites of action in spinal cord or brain; (b) the limitation of drug distribution to the desired site of action within the CNS (i.e., minimization of its movement into the vasculature); and (c) the availability of a vehicle which permits the delivery of large concentrations of drugs in relatively small volumes. Typically, administration of drugs by the neuraxial routes may be limited by their relative solubility in water or lipids and/or factors that govern their kinetics and make them less than fully effective. Thus, agents with high lipid partition coefficients may require unusual vehicles that are not routinely biocompatible. Similarly, such lipophilic agents may be cleared very rapidly after neuraxial administration, giving them a short residence time in spinal or brain tissue and leading to unacceptably high peripheral plasma or tissue concentrations. These characteristics may lead to the failure of a particular drug or significantly limit its utility. The development of a vehicle that can alter the rate at which agents may undergo redistribution, render the agent soluble, maintain its bioavailability, and be compatible with the neuraxis of a patient would be of particular significance.
The inventors are the first to recognize that the problems associated with neuraxial administration of drugs may be ameliorated by administering a drug or drugs to the neuraxis of a patient in the form of a complex between the drug and a cyclodextrin. Cyclodextrin complexes with other types of drugs and/or for other routes of administration have previously been known. For example, U.S. Pat. No. 4,869,904 is directed to a sustained release drug preparation made up of an inclusion complex between a drug and a cyclodextrin derivative. Neuraxial administration of these prior complexes was not reported. In contrast to this prior work, the present applicants have discovered that complexes between cyclodextrins and drugs, when administered to the neuraxis of a patient, can, inter alia, reduce or retard diffusion or passage of the drug into the vasculature of a patient and, in some cases, increase the effectiveness of the drug in vivo.
Pitha, J., et al. Life Sciences 43:493-502 (1988), discusses the use of cyclodextrin derivatives to dissolve drugs. In one portion of this paper, it discloses intracerebral injection of a cyclodextrin derivative complexed with alkylating pindolol. In contrast to the present invention, alkylating pindolol is not a therapeutic drug, so its complex with the derivatized cyclodextrin is not a drug:cyclodextrin complex as used herein. More importantly, this prior reference does not disclose any advantages of administering a drug:cyclodextrin complex to the neuraxis of a patient.
Another prior publication of interest, Kawasaki, A. et al. Pharmacokinetics 8:61-63 (1974), discusses pharmacological studies on .beta.-cyclodextrin clathrate compounds with prostagladin E.sub.2. In this work, the prostaglandin molecule was administered to animals by a variety of routes, including oral, intravenous and intracisternal. However, these authors concluded that .beta.-cyclodextrin showed no effect in their system. It is important to note that the cyclodextrins used to form drug complexes for the purposes herein must be derivatized relative to the parent cyclodextrin as will be discussed further herein. The cyclodextrin molecule used in this prior publication was unsubstituted.
Applicants are not aware of any prior reports of administration of complexes between drugs and substituted cyclodextrins to the neuraxis of a patient, as disclosed in greater detail herein below.